Prostate cancer is the most common cancer among men, with approximately 220,000 cases and 29,000 deaths annually in the United States. A significant proportion of men diagnosed with prostate cancer have metastatic disease. Further, metastases eventually develop in many other prostate cancer patients despite treatment with surgery or radiotherapy. Bone is the most common site of prostate cancer metastasis, and is also a site to which breast cancers and lung cancers often metastasize. Most prostate cancer metastases are androgen-dependent, so that there is a rapid response to surgical or medical castration, but in virtually all patients, the tumor eventually becomes androgen-independent, leading to significant morbidity and mortality. Once bone metastases occur, currently available therapies have limited effect. The most effective approved therapy that has been described for metastatic prostate cancer (administration of docetaxel) extends median survival approximately three months. (Petrylak et al., 2004, N. Engl. J. Med. 351:1513; Tannock et al., 2004, N. Engl. J. Med. 351:1502) Accordingly, new therapies for metastatic bone cancers are urgently needed.
The insulin-like growth factor receptor (IGF-IR) is a ubiquitous transmembrane tyrosine kinase receptor that is essential for normal fetal and post-natal growth and development. IGF-IR is located on the cell surface of most cell types and serves as the signaling molecule for growth factors IGF-I and IGF-II (collectively termed henceforth IGFs). IGF-IR can stimulate cell proliferation, cell differentiation, changes in cell size, and protect cells from apoptosis. It has also been considered to be quasi-obligatory for cell transformation (reviewed in Adams et al., Cell. Mol. Life Sci. 57:1050-93 (2000); Baserga, Oncogene 19:5574-81 (2000)). High levels of expression of IGF-IR have been reported in tissue samples from prostate cancer bone metastases. Bone contains the largest store of IGFs in the body.
IGF-IR is a pre-formed hetero-tetramer containing two alpha and two beta chains covalently linked by disulfide bonds. The receptor subunits are synthesized as part of a single polypeptide chain of 180 kd, which is then proteolytically processed into alpha (130 kd) and beta (95 kd) subunits. The entire alpha chain is extracellular and contains the site for ligand binding. The beta chain possesses the transmembrane domain, the tyrosine kinase domain, and a C-terminal extension that is necessary for cell differentiation and transformation, but is dispensable for mitogen signaling and protection from apoptosis.
IGF-IR is highly similar to the insulin receptor (IR), particularly within the beta chain sequence (70% homology). Because of this homology, recent studies have demonstrated that these receptors can form hybrids containing one IR dimer and one IGF-IR dimer (Pandini et al., Clin. Canc. Res. 5:1935-19 (1999)). The formation of hybrids occurs in both normal and transformed cells and the hybrid content is dependent upon the concentration of the two homodimer receptors (IR and IGF-IR) within the cell. Although hybrid receptors are composed of IR and IGF-IR pairs, the hybrids bind selectively to IGFs, with affinity similar to that of IGF-IR, and only weakly bind insulin (Siddle and Soos, The IGF System. Humana Press. pp. 199-225. 1999). These hybrids therefore can bind IGFs and transduce signals in both normal and transformed cells.
A second IGF receptor, IGF-IIR, or mannose-6-phosphate (M6P) receptor, also binds IGF-II ligand with high affinity, but lacks tyrosine kinase activity (Oates et al., Breast Cancer Res. Treat. 47:269-81 (1998)). Because it results in the degradation of IGF-II, it is considered a sink for IGF-II, antagonizing the growth promoting effects of this ligand. Loss of the IGF-IIR in tumor cells can enhance growth potential through release of its antagonistic effect on the binding of IGF-II with the IGF-IR (Byrd et al., J. Biol. Chem. 274:24408-16 (1999)).
Platelet derived growth factor receptors alpha and beta (PDGFRα and PDGFRβ) are type III receptor tyrosine kinases. PDGFRα is critical for development and fulfills important functions into adulthood. For example, mice homozygous for a null mutation die during embryogenesis. At later stages of development, PDGFRα is expressed in many mesenchymal structures, whereas adjacent epithelial cells produce platelet derived growth factors (PDGFs). Tissue samples from normal or hyperplastic prostate glands test negative for PDGFRα, whereas primary prostate tumors and skeletal masses from matched subjects express PDGFRα. Further, of prostate cell lines obtained from different metastatic sites, PDGFRα is found in bone metastasis-derived PC3 cells, but not in cell lines obtained from lymph node (LNCaP) and brain (DU-145) metastases.
The platelet-derived growth factor family of growth factors consists of five different disulphide-linked dimers, PDGF-AA, -BB, -AB, -CC, and -DD, that act via PDGFRα and PDGFRβ. These growth factors are dimeric molecules composed of disulfide-linked polypeptide chains that bind to two receptor proteins simultaneously and induce receptor dimerization, autophosphorylation, and intracellular signaling. PDGFRα and PDGFRβ are structurally similar and can form heterodimers as well as homodimers. Because PDGFRβ does not bind the PDGF-A chain with high affinity, PDGF-AA activates only αα receptor dimers, whereas PDGF-AB and PDGF-CC activates αα and αβ receptor heterodimers.